Only one-quarter of our bipolar outpatients show an adequate clinical prophylactic response in double-blind, randomized, one-year trials of lithium or carbamazepine monotherapy. Even with the combination of lithium and carbamazepine, only 50% of these outpatients respond. With the additional use of valproate, 40% of patients still remain unresponsive. It is from this pool of treatment-refractory patients that the Branch seeks to better understand the differential pathophysiological mechanisms in recurrent unipolar and bipolar affective disorders and develop new therapeutic modalities. The major new treatment initiative in the Branch is the use of repeated transcranial magnetic stimulation (rTMS) of the brain. Two of the first six patients responded in a pilot study of 20 Hz stimulation at 80% of motor threshold of left frontal cortex (George et al, 1995, NeuroReport). A double-blind, randomized, crossover trial indicated significant antidepressant effects of active rTMS for two weeks compared with the sham (George et al, 1998, Am J Psychiatry). The next study, now completed, assessed the differential responsivity to low-frequency (1 Hz) versus higher frequency (20 Hz) rTMS vs. sham stimulation over left frontal cortex at 80% of motor threshold. These data in 15 subjects suggest differential responses within the same patient to these different frequencies. Moreover, those with a pattern of baseline hypometabolism tend to respond to the 20 Hz stimulation, while those with baseline patterns of hypermetabolism are more likely to respond to the 1 Hz stimulation (Kimbrell et al, 1998). As the incidence and magnitude of clinical responsivity was not adequate for many patients, a fourth study using higher intensities (100% of motor threshold) has been initiated (18 patients enrolled) (Speer et al, 1998). This study replicated the findings of differential responsivity within individual patients and revealed that 20 Hz stimulation increases 0-15 blood flow while 1 Hz rTMS decreases it. A further controlled study in normal volunteers has confirmed that 1 Hz rTMS over frontal cortex induces relative decrements in bilateral frontal and striatal metabolism on PET. A major inpatient pharmacological study involves a double-blind, randomized trial of six weeks of treatment with an agent that enhances inhibitory GABAergic function (gabapentin [GPN]), versus any that decreases excitatory glutamatergic function (lamotrigine [LTG]), versus placebo, with patients crossing over to the other drug treatments in order to ascertain differential clinical response. This study, involving 37 patients, has been favorably reviewed by the Archives of General Psychiatry and found significant benefit of LTG (53% response rate) over GPN (27%) and placebo (22%) (Frye et al, 1998). Preliminary evidence suggests that baseline patterns of perfusion on 0-15 PET interacted with clinical response to both of these agents. Responders were low at baseline and increased with treatment, while nonresponders were in the normal range and showed decreases. A double-blind, randomized trial of T3 versus TRH versus placebo augmentation of venlafaxine is examining whether TRH can accelerate the rapidity of antidepressant onset. In relationship to predictors, preliminary evidence indicates that depressed patients with global hypermetabolism on PET, especially in the left insula, are more likely to be responsive to carbamazepine (N = 26), while those with the more classic pattern of frontal and left insular hypometabolism are more likely to be responsive to the dihydropyridine L-type calcium channel blocker nimodipine. We have found that nimodipine increases somatostatin in cerebrospinal fluid (CSF) and that those with lower CSF somatostatin at baseline tend to be more likely to respond clinically to these nimodipine-induced increases. Thus, a number of promising and mechanistically novel treatment approaches have been pioneered in the Branch and additional effort will be aimed at defining optimal parameters for rTMS response and the elucidation of clinical and neurobiological markers of such response. This and related work on the development of new treatment approaches for refractory bipolar patients is also being pursued on a wider basis with the establishment of the first NIMH-Stanley Foundation-supported Bipolar Treatment Outcome Network with multiple sites in the U.S. and one in Europe. This clinical trials Network addresses most of the recommendations of the NIMH 1989 and 1994 meetings on bipolar illness.